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PET-evaluated transport of [11C]hydroxyurea across the rat blood-brain barrier -: lack of influence of cyc-losporin and probenecid
Uppsala Imanet, GE Healthcare. (Hammarlund-Udenaes)
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2007 (English)In: Drug Metabolism Letters, ISSN 1872-3128, Vol. 1, no 3, 189-194 p.Article in journal (Refereed) Published
Abstract [en]

The transport of hydroxyurea, a ribonucleoside reductase inhibitor, over biological membranes is slow and it has therefore been suggested that the substance could interact with an active efflux transporter. The transport of [11C]hydroxyurea into the rat brain was therefore studied after administration of the multidrug resistance protein inhibitor probenecid (50 and 150 mg/kg), the P-glycoprotein inhibitor cyclosporin A (25 mg/kg), hydroxyurea (50, 150 and 450 mg/kg) and mannitol (25%). None of the intervention drugs affected the brain uptake of [11C]hydroxyurea. The brain-toplasma concentration ratios (Kp), with or without intervention drug, were in the range 0.12-0.25 after 60 min of [11C]hydroxyurea infusion. [11C]Verapamil, a P-glycoprotein substrate with low brain penetration, was used to study the ability of hydroxyurea to inhibit P-glycoprotein. Administration of hydroxyurea (150 and 450 mg/kg) did not increase brain concentrations of [11C]verapamil. It is therefore unlikely that hydroxyurea is a substrate for or an inhibitor of Pglycoprotein or a substrate for a probenecid sensitive transport system. The low brain concentrations may instead be the result of slow uptake due to the hydrophilic nature of hydroxyurea.


Place, publisher, year, edition, pages
2007. Vol. 1, no 3, 189-194 p.
Keyword [en]
PET, [11C]hydroxyurea, [11C]verapamil, pharmacokinetics, blood-brain barrier, active efflux
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-96872DOI: 10.2174/187231207781369799PubMedID: 19356042OAI: oai:DiVA.org:uu-96872DiVA: diva2:171599
Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2012-12-04Bibliographically approved
In thesis
1. Blood-Brain Barrier Transport: Investigation of Active Efflux using Positron Emission Tomography and Modelling Studies
Open this publication in new window or tab >>Blood-Brain Barrier Transport: Investigation of Active Efflux using Positron Emission Tomography and Modelling Studies
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis examines the transport of exogenous molecules across the blood-brain barrier (BBB), focusing on active efflux, using positron emission tomography (PET), computer simulation and modelling. P-glycoprotein (P-gp) inhibition was studied using [11C]verapamil and [11C]hydroxyurea was investigated as a new marker for active efflux transport. Simulations were carried out to explore the importance of the efflux transporter location in the BBB. Brain concentrations of [11C]verapamil, [11C]GR205171 and [18F]altanserin were compared in various laboratory animal species and in humans.

A central aspect of the studies has been the novel combination of dynamic PET imaging of the brain pharmacokinetics of a labelled drug, administered through an exponential infusion scheme allowing time-resolved consequence analysis of P-gp inhibition, and mathematical modelling of the obtained data. The methods are applicable to drugs under development and can be used not only in rodents but also in higher species, potentially even in humans, to investigate the effects of P-gp or other transporters on drug uptake in the brain.

The inhibition of P-gp by cyclosporin A (CsA) and the subsequent change in brain concentrations of [11C]verapamil occurred rapidly in the sense that [11C]verapamil uptake increased rapidly after CsA administration but also in the sense that the increased uptake was rapidly reversible. The P-gp inhibition was best described by an inhibitory indirect effect model in which CsA decreased the transport of [11C]verapamil out of the brain. The model indicated that approximately 90% of the transport of [11C]verapamil was P-gp-mediated. The low brain concentrations of [11C]hydroxyurea appeared to be a result of slow transport across the BBB rather than active efflux. This exemplifies why the extent and the rate of brain uptake should be approached as two separate phenomena. The brain-to-plasma concentration ratios for the three studied radiotracers differed about 10-fold be-tween species, with lower concentrations in rodents than in humans, monkeys and pigs. The increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species.

The findings demonstrate a need to include the dynamics of efflux inhibition in the experimental design and stress the importance of the choice of species in preclinical studies of new drug candidates.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 66 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 70
Pharmaceutical biosciences, pharmacokinetics, P-glycoprotein, blood-brain barrier, modelling, PET, active efflux, species differences, [11C]verapamil, drug development, Farmaceutisk biovetenskap
National Category
Medical and Health Sciences
urn:nbn:se:uu:diva-8562 (URN)978-91-554-7126-2 (ISBN)
Public defence
2008-04-18, B42, Biomedicinskt Centrum (BMC), Husargatan 3, Uppsala, 09:15
Available from: 2008-03-26 Created: 2008-03-26 Last updated: 2012-11-22Bibliographically approved

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Syvänen, Stina
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